Lithium, Stress, and Resilience in Bipolar Disorder: Deciphering this key homeostatic synaptic plasticity regulator

Lithium is the lightest metal and the only mood stabilizer that has been used for over half a century for the treatment of bipolar disorder (BD). As a small ion, lithium is omnipresent, and consequently, its molecular mechanisms and targets are widespread. Currently, lithium is a crucial pharmacotherapy for the treatment of acute mood episodes, prophylactic therapy, and suicide prevention in BD. Besides, lithium blood level is the most widely used biomarker in clinical psychiatry. The concept of stress in BD characterizes short- and long-term deleterious effects at multiple levels (from genes to behaviors) and the ability to establish homeostatic regulatory mechanisms to either prevent or reverse these effects. Within this concept, lithium has consistently shown anti-stress effects, by normalizing components across several levels associated with BD-induced impairments in cellular resilience and plasticity.

A literature search for biomarkers associated with lithium effects at multiple targets, with a particular focus on those related to clinical outcomes was performed. An extensive search of the published literature using PubMed, Medline and Google Scholar was performed. Example search terms included lithium, plasticity, stress, efficacy, and neuroimaging. Articles determined by the author to focus on lithium's impact on neural plasticity markers (central and periphery) and clinical outcomes were examined in greater depth. Relevant papers were evaluated, selected and included in this review.

Lithium induces neurotrophic and neuroprotective effects in a wide range of preclinical and translational models. Lithium's neurotrophic effects are related to the enhancement of cellular proliferation, differentiation, growth, and regeneration, whereas its neuroprotective effects limit the progression of neuronal atrophy or cell death following the onset of BD. Lithium's neurotrophic and neuroprotective effects seem most pronounced in the presence of pathology, which again supports its pivotal role as an active homeostatic regulator.

Few studies associated with clinical outcomes. Due to space limitations, the author was unable to detail all findings, in special those originated from preclinical studies.

These results support a potential role for biomarkers involved in neuroprotection and activation of plasticity pathways in lithium's clinical response. Evidence supporting this model comes from results evaluating macroscopic and microscopic brain structure as well neurochemical findings in vivo from cellular to sub-synaptic (molecules and intracellular signaling) compartments using central and peripheral biomarkers. Challenges to precisely decipher lithium's biological mechanisms involved in its therapeutic profile include the complex nature of the illness and clinical subtypes, family history and comorbid conditions. In the context of personalized medicine, it is necessary to validate predictive biomarkers of response to lithium by designing longitudinal clinical studies during mood episodes and associated clinical dimensions in BD.